Angiogenesis is the biological process of producing new blood vessels by sprouting a new branch from an existing blood vessel. While angiogenesis is essential for normal development and growth, it rarely occurs in adulthood except under strictly regulated circumstances (e.g., wound healing; see, for example, Moses et al., Science, 248:1408-1410, 1990). Angiogenesis also occurs in a number of diseases, such as cancer, in which new vessels are formed to support the growth and proliferation of both primary and metastatic tumors.
Blood vessels contain endothelial cells surrounded by a basement membrane. One of the first steps in angiogenesis is the degradation of the basement membrane by proteolytic enzymes produced by endothelial cells to form a breach in the membrane through which endothelial cells can migrate and proliferate to form a new vessel sprout. This step can be initiated as follows. First, components of the plasminogen activator (PA)-plasmin system stimulate a protease cascade that results in high concentrations of plasmin and active matrix metalloproteinases (MMPs) at the site of angiogenesis. This increased proteolytic activity leads to degradation of the extracellular matrix (ECM) and invasion of the vessel basal lamina. The release of ECM degradation products leads to chemotaxis of endothelial cells.
Numerous pathological conditions are associated with unwanted angiogenesis. For example, tumors can induce angiogenesis in order to grow beyond minimal size and to metastasize (Hanahan and Folkman Cell 1996, 86:353-64). Tumor development is associated with increased release of angiogenesis factors, most prominently of vascular endothelial growth factor (VEGF) (Brown LF et al., Exs 1997, 79:233-69). Other disorders characterized by unwanted angiogenesis include, for example, tissue inflammation, arthritis, diabetic retinopathy, and macular degeneration by neovascularization of retina (see, e.g., Folkman et al., Science, 235:442-447, 1987).
The endotheliases are a class of membrane proteases that are expressed on cells, particularly endothelial cells.